This invention relates to ophthalmic compositions, in particular, those for treatment of corneal lesions, those for treatment of deteriorated corneal esthesia, those for treatment of dry eye syndrome, and those for treatment of hypolacrimation.
Corneal lesions are caused by defects in the corneal tissue. Defects in the epithelium generally give rise to subjective symptoms including foreign body sensation, eye pain, photophobia, tear secretion, etc. Defects in the corneal tissue are called epithalaxia or erosion when they are restricted only in the epithelium, and corneal ulcer when they extend from the Bowman""s membrane to the parenchyma.
There are various possible factors involved in corneal lesions, including pathological factors such as diabetes, inflammation, allergy, microorganisms (virus, bacteria, fungi, etc.) etc., chemical factors such as cytotoxicity by chemicals, caustic effect by acids or alkalis, etc., and physical factors such as dryness (dry eye syndrome, etc.) and trauma due to foreign bodies (contact lens, etc.), burn, etc. It has recently been reported that antiseptics contained in eye drops such as benzalkonium chloride and chlorobutanol, antibiotics of the aminoglycoside series, non-steroidal antiphlogistics, IDU, pimaricin, etc. impair the corneal epithelium.
Various treatments have been attempted depending on the site affected and the severity of the corneal lesion. In addition to physical treatments such as instillation of antibiotic-containing ointment plus pressure eye-patch treatment, use of therapeutic soft contact lens, and corneal superficial puncture, instillation of fibronectin, hyaluronic acid, or a high osmotic agent is currently employed. From the viewpoint of treatment of diabetic complications, it has been reported that aldose reductase inhibitors are effective in treatment of diabetic corneal lesions. However, for example in cases where the symptoms have become aggravated so that the keratoepithelium becomes detached from the corneal parenchyma, satisfactory recovery cannot be attained at present with any of the treatments described above. Thus the treatments desired are those effective even in considerably progressive corneal lesions where the epithelium has been detached or defected.
The cornea is one of the most sensitive tissues on the body surface, and sensory nerve endings are distributed all over the cornea. Therefore when the corneal esthesia remains normal, the patient can notice the pain due to pathological conditions or lesions in cornea. When the corneal esthesia is deteriorated, however, no subjective symptoms are noticed and this promotes to further aggravation of the corneal lesions.
Factors that are known to deteriorate corneal esthesia include aging, diseases (corneal herpes, diabetes, etc.), use of contact lens, and ophthalmologic surgery (surgery for cataract, corneal transplantation, surgery for retinal detachment, etc.). Not only for treatment but also for prevention of progress of the pathological conditions, treatments that may normalize the subjective symptoms of the patients, i.e. agents that may improve the deteriorated corneal esthesia due to various diseases are being desired.
One of the opthalmologic symptoms that became lately the center of wide interest is dry eye syndrome. Dry eye syndrome is defined as xe2x80x9cthe condition where the tear quantity has been decreased or tear quality has become abnormal, irrespective of whether the keratoconjunctival lesion is present or absentxe2x80x9d (Yamada, N., et al., Folia Ophthalmol Jpn., 43, 1289-1293 (1992)), including dry eye syndrome noted in diseases such as hypolacrimation, alacrima, xerophthalmia, Sjogren""s syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, ocular pemphigoid, marginal blepharitis, diabetes, etc. dry eye syndrome noted after surgery for cataract, or accompanied with allergic conjunctivitis, etc., and dry eye syndrome observed in hypolacrimation due to increased VDT (visual display terminal) tasks or dry air in an air-conditioned room.
There are various causes of dry eye syndrome some of which remain unidentified. Dry eye syndrome is treated only by administration of artificial tears for increase of the quantity of tear retained within the conjunctival sac to relieve the subjective symptoms, or by prevention of eyes from drying. It has been desired that substances capable of bringing about satisfactory treatment including improvement of hypolacrimation are provided.
Tear secretion is classified into basal tear secretion and reflex tear secretion. Basal tear secretion means tear secretion under ordinary conditions with the eyelid open, being considered to be mainly from the accessory lacrimal glands (Krause gland, Wolfring gland, etc.). On the other hand, reflex tear secretion means tear secretion in the presence of some stimulation to the keratoconjunctival surface, nasal mucosa, etc. or accompanied with mental changes such as grief and joy. It is considered to be from the main lacrimal gland. Therefore improvement of decreased basal tear secretion, i.e. tear secretion under ordinary conditions with the eyelid open, is particularly important as judged from the symptoms of dry eye syndrome.
This invention intends to solve the problems described above, and one of the objectives is to provide ophthalmic compositions effective in treatment of at least one disease selected among corneal lesion, deteriorated corneal esthesia, dry eye syndrome, and hypolacrimation.
The inventors have eventually found as the result of their researches that the compounds represented by the general formula (I): 
wherein, A and B are independently lower alkylene, and X, Y, and Z are independently halogen, are excellent improvement of diabetic corneal lesion and deteriorated corneal esthesia.
The inventors have also found that the compounds capable of inhibiting aldose reductase including the compounds represented by the above-mentioned general formula (I) are excellent in improvement not only of diabetic corneal lesion but also of non-diabetic corneal lesions, and that the compounds are excellent in improvement of dry eye syndrome, especially hypolacrimation including diminished basal tear secretion. Thus, they completed this invention.
The invention is explained in detail in the following.
(1) An ophthalmic composition for treatment of diabetic corneal lesion and/or for treatment of deteriorated corneal esthesia of which comprises, as an active ingredient, a compound represented by the general formula (I): 
wherein, A and B are independently lower alkylene and X, Y, and Z are independently halogen (named the compound hereinafter), or a pharmacologically acceptable salt thereof.
(2) The ophthalmic composition described in (1) wherein in the general formula (I) A and B are independently methylene, X is chlorine, Y is bromine, and Z is fluorine atom.
(3) The ophthalmic composition described in (1) or (2) that are used for treatment of diabetic corneal lesion.
(4) The ophthalmic composition described in (1) or (2) that are used for treatment of deteriorated corneal esthesia.
(5) The ophthalmic composition described in any of (1) to (4) that are in the form of preparations for eye local administration.
(6) An ophthalmic composition for treatment of non-diabetic corneal lesions which comprises, as an active ingredient, an aldose reductase inhibitor.
(7) An ophthalmic composition for treatment of dry eye syndrome, which comprises, as an active ingredient, an aldose reductase inhibitor.
(8) An ophthalmic composition for treatment of hypolacrimation, which comprises, as an active ingredient, an aldose reductase inhibitor.
(9) The ophthalmic composition described in any of (6) to (8), wherein the aldose reductase inhibitor is a compound represented by the general formula (I): 
wherein A and B are independently lower alkylene, and X, Y, and Z are independently halogen, or a pharmacologically acceptable salt thereof.
(10) The ophthalmic composition described in (9), wherein A and B are methylene, X is chlorine, Y is bromine, and Z is fluorine.
(11) The ophthalmic composition described in any of (6) to (10) which are in the form of preparations for eye local administration.
(12) A method for treating diabetic corneal lesion and/or deteriorated corneal esthesia which comprises administering an effective amount of a compound represented by the general formula (I): 
wherein A and B are independently lower alkylene, and X, Y, and Z are independently halogen, or a pharmacologically acceptable salt thereof, to a subject in need of a treatment of diabetic corneal lesion and/or deteriorated corneal esthesia.
(13) A method for treating non-diabetic corneal lesion which comprises administering an effective amount of an aldose reductase inhibitor to a subject in need of a treatment of non-diabetic corneal lesion.
(14) A method for treating dry eye syndrome which comprises administering an effective amount of an aldose reductase inhibitor to a subject in need of a treatment of dry eye syndrome.
(15) A method for treating hypolacrimation which comprises administering an effective amount of an aldose reductase inhibitor to a subject in need of a treatment of hypolacrimation.
(16) Use of a compound represented by the general formula (I): 
xe2x80x83wherein A and B are independently lower alkylene, and X, Y, and Z are independently halogen, or a pharmacologically acceptable salt thereof, in the manufacture of an ophthalmic composition for the treatment of diabetic corneal lesion and/or deteriorated corneal esthesia.
(17) Use of an aldose reductase inhibitor in the manufacture of an ophthalmic composition for the treatment of non-diabetic corneal lesion.
(18) Use of an aldose reductase inhibitor in the manufacture of an ophthalmic composition for the treatment of dry eye syndrome.
(19) Use of an aldose reductase inhibitor in the manufacture of an ophthalmic composition for the treatment of hypolacrimation.
The terms in the general formula (I) of this specification are defined as follows:
A and B are independently lower alkylene. Lower alkylene as used in this specification mean straight or branched alkylene groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. In the concrete, they are methylene, ethylene, trimethylene, propylene groups, and the like, among which methylene and ethylene groups are desirable.
X, Y, and Z are independently halogen (chlorine, bromine, fluorine, iodine), and it is particularly desirable when X is chlorine, Y is bromine, and Z is fluorine.
In this invention the compound of the formula (II): 
having methylene for each of A and B, chlorine for X, bromine for Y, and fluorine for Z in the general formula (I), i.e. [3-(4-bromo-2-fluorobenzyl)-7-chloro2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl]acetate, is particularly suitable.
The compound and pharmacologically acceptable salts thereof included in this invention as the active ingredient are publicly known compounds, which can be produced for example with the method described in the Japanese Published Unexamined Patent Publication No. Sho 62-96476 (European Patent Publication No. 0218999, U.S. Pat. No. 4,734,419) or a method based on this method.
Pharmacologically acceptable salts of the compound in this invention include salts with basic compounds such as inorganic bases (e.g. sodium, potassium, calcium, magnesium, aluminum, ammonium, etc.), and organic bases (e.g. primary amines such as ethanolamine; secondary amines such as diethylamine, diethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine , etc.; tertiary amines such as trimethylamine, triethylamine, pyridine, picoline, triethanolamine, etc.; and so on) and the like.
The compound and pharmacologically acceptable salts thereof are effective in prevention, cure, relief/arrestation/relief of development of symptoms of diabetic corneal lesions, and in improvement of deteriorated corneal esthesia in mammals including man, ox/cow, horse, dog, mouse, and rat etc., being the active ingredient in the ophthalmic composition comprising preparations for treatment of diabetic corneal lesion and/or those for treatment of deteriorated corneal esthesia in mammals.
This invention also provides ophthalmic compositions of which active ingredient is an aldose reductase inhibitor. The fact that compounds that can inhibit aldose reductase are excellent in treatment of non-diabetic corneal lesions as well as symptoms of dry eye syndrome, particularly hypolacrimation including decreased basal tear secretion, is a new finding.
Aldose reductase inhibitors included in this invention as the active ingredient are not specified if they can inhibit aldose reductase, being exemplified in the concrete by the compounds represented by the general formula (I), particularly the compound of the formula (II), and also by epalrestat, ponalrestat, tolrestat, sorbinil, methosorbinil, imirestat, 2,3-dihydro-2,8-bis(1-methylethyl)-3-thioxo-4H-1,4-benzoxazine-4-acetic acid (AD5467), 6-fluoro-2,3-dihyro-2xe2x80x2,5xe2x80x2-dioxo-(2S-cis)-spiro[4H-1-benzopyran-4,4xe2x80x2-imidazolidine]-2-carboxyamide (SNK-860), 8-chloro-2xe2x80x2,3xe2x80x2-dihydrospiro[pyrolizine-3,6xe2x80x2(5,H)-pyrolo[1,2,3-de]-[1,4]benzoxazine]2,5,5xe2x80x2-trion (ADN138), and 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedion (CT-112), etc. Particularly suitable are the compounds represented by the general formula (I) especially the compounds shown by the formula (II).
Aldose reductase inhibitors are effective in prevention, cure, relief/arrestation/relief of development of symptoms of diabetic corneal lesion, and in cure of symptoms of dry eye syndrome, particularly in improvement of hypolacrimation including decreased basal tear secretion in mammals including man, ox/cow, horse, dog, mouse, and rat, etc. They are the active ingredient in the ophthalmic composition for mammals comprising preparations for treatment of non-diabetic corneal lesion, for treatment of dry eye syndrome, and/or for treatment of hypolacrimation.
As described above, diabetic corneal lesion in this invention means various corneal lesions derived from diabetes, including, in the concrete, diabetic punctate superficial keratoepitheliosis, diabetic recurrent erosion of keratoepithelium, and diabetic delayed defect of keratoepithelium. Non-diabetic corneal lesions are, as described above, those caused by non-diabetic pathological, such as inflammation, allergy, microorganisms, chemicals, caustic effect of acids or alkalis, dryness, foreign bodies, burn, etc. Deteriorated corneal esthesia in this invention means the pathological conditions where the corneal esthesia has been deteriorated as the result of aging, diseases such as corneal herpes and diabetes, etc., use of contact lens, and ophthalmologic surgery (surgery for cataract, corneal transplantation, surgery for retinal detachment, etc.). Diseases accompanied with dry eye syndrome include, as described above, hypolacrimation, alacrima, xerophthalmia, Sjxc3x6gren""s syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, ocular pemphigoid, marginal blepharitis diabetes, etc. and dry eye syndrome is also noted after surgery for cataract, or accompanied with allergic conjunctivitis, etc. Dry eye syndrome is observed in hypolacrimation due to increased VDT tasks or dry air in air-conditioned rooms.
Hypolacrimation means abnormal (decreased or stopped) tear secretion due to some causes, including abnormal basal tear secretion.
Treatment with the ophthalmic composition includes all controls, including prevention, cure, relief/arrestation/relief of development, etc. The treatment of corneal lesion is also effective in intractable corneal lesion in advanced conditions, i.e. with advanced erosion or detachment.
Ophthalmic compositions of this invention may be administered orally or parenterally, but use in the form of preparations for eye local administration is particularly desirable when the avoidance of the influence on other areas of the cardiovascular system and the significance of their actual effectiveness, etc. are taken into account.
Such dosage forms include eye drops, eye ointments, powders, granules, tablets, capsules, injections, etc., among which eye drops and eye ointments are particularly suitable. Preparations in such dosage forms can be produced with the conventional means.
Aqueous solutions and diluents for suspensions used in preparation of eye drops are distilled water, physiological saline, and the like, and non-aqueous solutions and diluents for suspensions include vegetable oil, liquid paraffin, mineral oil, propylene glycol, p-octyldodecanol, etc.
In addition, various additives may be contained in eye drops as needed, including buffering agents, isotonizers, preservatives, thickeners, stabilizers, antioxidants, pH-adjusting agents, chelating agents, etc. Buffering agents are added to keep the pH constant, for example at 5.0 to 8.0, including borate buffer, citrate buffer, tartrate buffer, phosphate buffer, acetate buffer, etc. Such a buffer is added in an amount that is suitable for the purpose of buffering, i.e. that can keep the pH value constant in the range as described above.
Isotonizers are added to make the preparation isotonic with the tear, including sugars such as glucose, mannitol, sorbitol, etc.; polyhydric alcohols such as glycerol, polyethylene glycol, propylene glycol, etc.; and salts such as sodium chloride, sodium citrate, etc. Such an isotonizer is added in an amount that makes the osmotic pressure of the eye drop equal to that of the tear. Preservatives used are benzalkonium chloride, parabens, chlorobutanol, etc. As pointed out above, some preservatives such as benzalkonium chloride, chlorobutanol, etc. have been reported to impair the cornea, but these preservatives may be added because the preparations of this invention are capable of improving the corneal lesion.
Thickeners that can be used include glycerol, carboxymethyl cellulose, carboxyvinyl polymers, etc.; stabilizers such as sodium sulfite, propylene glycol, etc.; antioxidants such as ascorbic acid, sodium ascorbate, tocopherol, sodium thiosulfate, etc.; pH-adjusting agents such as hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc.: and chelating agents such as sodium edetate, sodium citrate, etc.
Eye drops are prepared by aseptic manipulation, or sterilization is performed at a suitable stage of preparation.
Eye ointments can be aseptically prepared by mixing the active ingredient into the base usually used for preparation of eye ointments followed by formulation into pharmaceutical preparations with a conventional method. Bases for eye ointments are exemplified by vaseline, jelene 50, plastibase, macrogol, etc., and surfactants may be added to increase hydrophilia. Additives described above, for example preservatives, may be contained in eye ointments as needed.
In addition, ingredients having pharmacological activity different from that of the ingredient of this invention may be added as needed to the pharmaceutical preparations of this invention if they are compatible to the purpose of the invention.
The dose and dosing frequency of the active ingredient of this invention vary according to the symptoms of the disease to be treated, age and body weight of the patient, dosage form, treatment duration, therapeutic effect desired, etc. In general, for local ophthalmic administration, it brings about a satisfactory effect for an adult, that in case of use as an eye drop, of the preparation containing 0.001 to 10.0 w/v %, preferably 0.01 to 1.0 w/v %, of the compound of this invention or a pharmacologically acceptable salt thereof or an aldose reductase inhibitor may be administered several times, preferably 1 to 6 times in an eye, a day and several drops, preferably 1 to 4 drops at a time, and in case of use as an eye ointment, of the preparation containing 0.001 to 10.0 w/v %, preferably 0.01 to 1.0 w/v %, of the compound of this invention or a pharmacologically acceptable salt thereof or an aldose reductase inhibitor may be applied several times, preferably 1 to 6 times in an eye, a day.
In this invention, one active ingredient alone or two or more active ingredients in combination may be contained in the preparation. In the preparation that contains two or more active ingredients, the amount of each ingredient may be determined appropriately according to the therapeutic effect and safety of each ingredient.